OVERALL: Summary/Abstract The overall goal of the MD Anderson SPORE in Gastrointestinal Cancer is to reduce mortality and morbidity rates from colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC), and to improve the quality of life of patients afflicted by these diseases. CRC is the 2nd most common cause of cancer-related deaths in this country, while PDAC is the 3rd most common cause, underscoring the significance of the work undertaken in this proposal. Our multidisciplinary team will conduct highly innovative translational research including first-in-human trials in order to further therapeutic options available to CRC and PDAC patients. The GI SPORE will be jointly led by Scott Kopetz and Anirban Maitra, who are accomplished translational researchers in CRC and PDAC, respectively. We propose the following three projects: Project 1 will test the efficacy of a novel personalized peptide vaccine in the adjuvant setting in post-resection CRC patients, and also evaluate in preclinical models the most optimal combination therapies for vaccination in this disease. Project 1 will be a collaboration with Johns Hopkins University, and represents the confluence of our shared expertise in cancer immunotherapy and immune correlatives. Project 2 will evaluate the role of oncogenic STAT3 signaling in chronic inflammation-associated and hereditary CRC, using a combination of genetically engineered animal models and patient-derived organoids (PDOs). In addition, this project will conduct a prevention study with an internally-developed STAT3 inhibitor. Project 3 will evaluate biological correlates of response and resistance (including metabolic imaging studies) to a novel inhibitor of oxidative phosphorylation (OXPHOS) in PDAC, using our substantial repertoire of genetically annotated patient-derived xenografts (PDXs). Further, we will evaluate this OXPHOS inhibitor, IACS-10759, in two clinical trials targeting metastatic and locally advanced PDAC patients, respectively, with accompanying novel imaging and molecular correlatives. An important objective of our program will be the recruiting of women and minorities to the field and mentoring of early career faculty through the Career Enhancement Program (CEP), and funding of innovative pilot projects through the Developmental Research Program (DRP). An Administrative Core designed to maintain fiscal responsibility along with reporting and institutional compliance will support all three projects. A Biospecimen and Pathology Core will support all clinical and research biospecimen needs for the three projects and a Biostatistics and Bioinformatics Core will provide support for trial design and biostatistics. Established working relationships have been extremely productive on many fronts from a well-positioned team approach. Our overall GI SPORE team is strategically organized to effectively translate our preclinical concepts and novel targets rapidly into a clinical setting, with the goal of significant impact on mortality rates from CRC and PDAC